Hormesis occurs when otherwise damaging stimuli produce beneficial effects after low dose applications. (Calabrese, E. J., and Baldwin, L. A., 1998. Hormesis as a biological hypothesis. Environ Health Perspect 106 Suppl 1357-36; Rattan, S. I., 2001, Applying hormesis in aging research and therapy. Hum Exp Toxicol 20(6), 281-285; discussion 293-284.) Several hormetic stimuli appear to promote life span extension. (Cypser, J. R. and Johnson, T. E., 2002. Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity. J. Gerontol A Biol Sci Med Sci 57(3):B109-114.) UV and ionizing radiation, temperature, hyper-gravity, and dietary restriction extend life span in diverse species. (Rattan, S. I., 2004a. Aging intervention, prevention, and therapy through hormesis. J Gerontol A Biol Sci Med Sci 59(7), 705-709.) Temperature modulation such as heat shock can promote hormetic effects as shown in other studies. (Verbeke, P., Clark, B. F., and Rattan, S. I., 2000. Modulating cellular aging in vitro: hormetic effects of repeated mild heat stress on protein oxidation and glycation. Exp Gerontol 35(6-7), 787-794.) Repeated mild heat-shock (RMHS) generates anti-aging hormetic effects on human fibroblasts undergoing in vitro senescence. (Fonager, J., Beedholm, R., Clark, B. F., and Rattan, S. I., 2002. Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro. Exp Gerontol 37(10-11), 1223-1228.) When in vitro senescence is delayed, progressive cell enlargement is retarded, abnormal proteins are prevented, reduced glutathione increases, and age-dependent glycocylation end products decline. (Rattan, S. I., 1998. Repeated mild heat shock delays ageing in cultured human skin fibroblasts. Biochem Mol Biol Int 45(4), 753-759; Verbeke, P., Clark, B. F., and Rattan, S. I., 2001a. Reduced levels of oxidized and glycoxidized proteins in human fibroblasts exposed to repeated mild heat shock during serial passaging in vitro. Free Radic Biol Med 31(12), 1593-1602; Verbeke, P., Deries, M., Clark, B. F., and Rattan, S. I., 2002. Hormetic action of mild heat stress decreases the inducibility of protein oxidation and glycoxidation in human fibroblasts. Biogerontology 3(1-2), 117-120.) Cellular anti-aging effects include maintenance of youthful morphology, increased levels of various heat shock proteins (Hsps), increased proteasomal activities, increased antioxidative abilities, and increased resistance to damage by ethanol, hydrogen peroxide, and UV-A irradiation (Parsons, Pa. The limit to human longevity: an approach through a stress theory of ageing. Mech Ageing Dev. 1996; 87: 211-8; Caratero, A, Courtade, M, Bonnet, L, Planel, H and Caratero, C. Effect of a continuous gamma irradiation at a very low dose on the life span of mice. Gerontology. 1998; 44: 272-6; Yukawa, 0, Nakajima, T, Yukawa, M, Ozawa, T and Yamada, T. Induction of radical scavenging ability and protection against radiation-induced damage to microsomal membranes following low-dose irradiation. Int J Radiat Biol. 1999; 75: 1189-99; Miura, Y, Abe, K, Urano, S, Furuse, T, Noda, Y, Tatsumi, K and Suzuki, S. Adaptive response and the influence of ageing: effects of low-dose irradiation on cell growth of cultured glial cells. Int J Radiat Biol. 2002; 78: 913-21; Khazaeli, A A, Tatar, M, Pletcher, S D and Curtsinger, J W. Heat-induced longevity extension in Drosophila. I. Heat treatment, mortality, and thermotolerance. J Gerontol A Biol Sci Med Sci. 1997; 52: B48-52). How these hormetic effects are achieved remain to be fully elucidated.
Many hormetic effects appear to be mediated, in part, by various components of the heat shock response (HSR). (Rattan, S. I., 2004b. Mechanisms of hormesis through mild heat stress on human cells. Ann N Y Acad Sci 1019554-558; Rattan, S. I., 2007. Hormesis in ageing. Ageing Res Rev August 31 (e pub)) As a primordial intracellular defense mechanism against stressful conditions, preferential transcription and translation of heat shock messenger RNA leading to short term hsp accumulation prepare cells for lethal and damaging results. (Hayes, S. A., and Dice, J. F., 1996. Roles of molecular chaperones in protein degradation. J Cell Biol 132(3), 225-258; Jindal, S., 1996. Heat shock proteins: applications in health and disease. Trends Biotechnol 14(1), 17-20; Udelsman, R., Blake, M. J., Stagg, C. A., and Holbrook, N. J., 1994. Endocrine control of stress-induced heat shock protein 70 expression in vivo. Surgery 115(5), 611-616.) Optimal HSR is beneficial for cell survival; whereas, inefficient and altered HSR results can result in abnormal growth, development, aging and apoptosis. (Rattan, S. I., and Derventzi, A., 1991. Altered cellular responsiveness during ageing. Bioessays 13(11), 601-606; Soti, C., and Csermely, P., 2000. Molecular chaperones and the aging process. Biogerontology 1(3), 225-233.) It appears that HSR declines during senescence due to a variety of factors, but mostly attributable to a decrease in Heat Shock Factor 1 (HSF1)-DNA binding. (Udelsman, R., Blake, M. J., Stagg, C. A., and Holbrook, N. J., 1994. Endocrine control of stress-induced heat shock protein 70 expression in vivo. Surgery 115(5), 611-616.) It is believed that the transcription factor HSF1 centrally modulates HSR. It is believed that in the absence of stress, HSF1 rests in an un-activated state and is constrained by self-folding and HSP90 juxtaposed as a molecular brake. It has been reported that HSP90 prevents HSF1-DNA binding. (Satyal, S. H., Chen, D., Fox, S. G., Kramer, J. M., and Morimoto, R. I., 1998. Negative regulation of the heat shock transcriptional response by HSBP1. Genes Dev 12(13), 1962-1974; Zou, J., Guo, Y., Guettouche, T., Smith, D. F., and Voellmy, R., 1998. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94(4), 471-480.) Different forms of stress can cause HSF1 to unfold, become hyper-phosphorylated, and form homo-trimers that acquire DNA binding capability. It has been reported that a possible cause of disrupted HSF1-Hsp90 complexes during stress is the accumulation of denatured polypeptides that attract Hsp90 from HSF1. (Bharadwaj, S., Ali, A., and Ovsenek, N., 1999. Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 in vivo. Mol Cell Biol 19(12), 8033-8041; Guo, Y., Guettouche, T., Fenna, M., Boellmann, F., Pratt, W. B., Toft, D. O., Smith, D. F., and Voellmy, R., 2001. Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. J Biol Chem 276(49), 45791-45799; Zou, J., Guo, Y., Guettouche, T., Smith, D. F., and Voellmy, R., 1998. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94(4), 471-480.) It has been reported that during stress recovery, HSF1 trimers reassociate with Hsp90 complexes. (Satyal, S. H., Chen, D., Fox, S. G., Kramer, J. M., and Morimoto, R. I., 1998. Negative regulation of the heat shock transcriptional response by HSBP1. Genes Dev 12(13), 1962-1974; Zou, J., Guo, Y., Guettouche, T., Smith, D. F., and Voellmy, R., 1998. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90) that forms a stress-sensitive complex with HSF1. Cell 94(4), 471-480.
At the organism level anti-aging and life-prolonging effects of heat shock have been reported for Drosophila (Khazaeli, A. A., Tatar, M., Pletcher, S. D., and Curtsinger, J. W., 1997. Heat-induced longevity extension if Drosophila. I. Heat treatment, mortality, and thermotolerance, J Gerontol A Biol Sci Med Sci 52(1), B48-52; Hercus, M. J., Loeschcke, V., and Rattan, S. I., 2003. Lifespan extension of Drosophila malanogaster through hormesis by repeated mild heat stress. Biogeront 44(3), 149-156; Sorensen, J. G., Kristensen, T. N., Kristensen, K. V., Loeschcke, V., 2007. Sex specific effects of heat induced hormesis in Hsf-deficient Drosophila melanogaster. Exp Gerontol 42(12), 1123-1129) and nematodes (Lithgow, G. J., 1996. Invertebrate gerontology: the age mutations of Caenorhabditis elegans. Bioessays 18(10), 809-815; Lithgow, G. J., White, T. M., Melov, S., and Johnson, T. E., 1995. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci USA 92(16), 7540-7544; Olsen, A., Vantipalli, M. C., Lithgow, G. J., 2006. Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments. Biogerontology 7(4): 221-230). Attempts to reproduce anti-aging effects in large mammalian organs pose an interesting challenge due to unintended external heat damage.
There is a continuing need in the art to identify safe and effective ways to treat diseases and provide anti-aging and life-prolonging effects.